Codeine is an opiate used for its analgesic, antitussive and antidiarrheal properties. It is by far the most widely used opiate in the world and very likely the most commonly used drug overall according to numerous reports over the years by organizations such as the World Health Organization.

Codeine is a natural alkaloid of the opium poppy plant Papaver somniferum L. but normally constitutes only a minor fraction of the total alkaloids e.g. typically only 5-20% of the level of morphine. While codeine can be extracted from opium and poppy straw, the demand for codeine far exceeds the current available natural supply so most of the codeine currently being manufactured (85-90 percent) is obtained from morphine through the process of O-methylation. The major part of the world's licit morphine production is to support the manufacture of codeine. If codeine could be sourced from non-morphine-containing poppies it would greatly decrease the growing of morphine poppies with the potential for diversion and abuse. Codeine is used to manufacture Active Pharmaceutical Ingredients (APIs) such as Codeine Phosphate, Codeine Sulphate, Codeine Hydrochloride and Codeine Base, which are in turn used to manufacture e.g. high-volume, over-the-counter, dosage forms for the relief of pain (analgesics) and cough (antitussives). Codeine is also the starting material and prototype of a large class of mainly mild to moderately strong opioids such as dihydrocodeine and hydrocodone and its derivatives such as nicocodeine and oxycodone. Thus catalytic hydrogenation of codeine yields dihydrocodeine (used to manufacture APIs such as Dihydrocodeine Tartrate) that in turn can be converted by Oppenauer oxidation to dihydrocodeinone (Hydrocodone, used to manufacture APIs such as Hydrocodone Bitartrate).
The industrial-scale methylation of morphine, at the phenolic hydroxyl group at position 3, to give codeine is usually conducted using quaternary ammonium methylating agents, typically trimethylphenylammonium chloride, in the presence of various bases such as alkali hydroxides, alkoxides, or carbonates/bicarbonates. Use of the quaternary ammonium methylating agent greatly diminishes the competing methylation of the alkaloid tertiary amine function which is a major problem with other methylating agents such as methyl halides or dimethyl sulphate, where the formation of the alkaloid quaternary salts causes loss of yield and the generation of other impurities such as alpha- and beta-codimethine via the Hofmann elimination reaction. However this solution to the quaternisation problem comes at the cost of generating the objectionally-odiferous and toxic byproduct N,N-dimethylaniline (DMA); this must be completely removed from the product and imposes waste disposal, occupational health and safety (OHS) and environmental concerns.
Most methylation procedures using trimethylphenylammonium reagents in essence involve the exposure of the trimethylammonium morphinate ion pair to high temperatures (exceeding 90 deg C.) in a non-polar, water-immiscible solvent such as toluene or xylene, where the ion pair rapidly collapses to codeine and DMA. The necessity for such solvents creates further OHS and environmental burdens on the manufacture and imposes costs associated with solvent recovery and purification. Under the vigorous conditions necessary, it is imperative that the stoichiometry of the reagents be carefully controlled to avoid on the one hand, undermethylation, leaving too much unreacted morphine, or on the other hand overmethylation, leading to formation of codeine-O(6)-methyl ether (“methylcodeine”). Both situations lead to yield losses both directly, through lower codeine formation, and indirectly through further codeine losses attending the removal of the unreacted morphine or the methycodeine impurities; morphine is relatively easy to remove e.g. by washing a toluene solution of the codeine with aqueous alkali but this process also sacrifices some codeine to the washes, while methylcodeine is difficult to remove and may require extensive processing to achieve desired limits. Another problematic impurity created by the synthesis from morphine is dimethylpseudomorphine, created by methylation of a common impurity in Concentrate of Poppy Straw Morphine, pseudomorphine (2,2′-bismorphine). Dimethylpseudomorphine is particularly difficult to remove from codeine and imposes high yield losses due to the additional processing required.
The manufacture of codeine from morphine requires extensive processing at some stage to remove colour bodies originating either in opium or in the Concentrate of Poppy Straw Morphine (CPS-M); in the latter case the colour bodies derive from the initial extraction process that produces morphine from poppy straw; the extraction conditions required to recover morphine from poppy straw are such that there is considerable, unavoidable extraction of coloured materials from the poppy and the CPS-M may typically have several percent of non-alkaloid material. With opium as input, the raw material is grossly impure (e.g. 5-24% morphine) and it is mandatory to purify and separate the morphine from the other alkaloids and colour bodies before input to codeine manufacture, while with Concentrate of Poppy Straw Morphine, some manufacturers upgrade the morphine to Technical quality before manufacture of codeine, while others enter the material directly into the methylation and then process to remove colour post-methylation; both approaches have considerable cost penalties associated with the additional processing, inevitable yield losses, capacity and opportunity costs. Codeine is more soluble than morphine in virtually all common media and is consequently easier to extract from poppies and easier to purify; hence the yield and quality and cost of natural codeine obtained from a codeine poppy are all improved relative to synthetic codeine obtained from natural morphine.
Alkaloids are extracted from the poppy capsules of Papaver somniferum by two commercial methods. In one method, the immature capsule is cut and the latex collected from the wound. The air-dried latex is opium which, according to the Merck Index, 11th edition, contains alkaloids in the amounts shown in Table I. In a second method, the mature poppy capsules and the poppy capsule stems are collected, and threshed to remove the seeds and form a straw. When necessary, the straw is dried to a water content below 16%. Solvent or water extraction is employed to remove the alkaloids from the straw. For the varieties of Papaver somniferum normally grown, the straw, on a dry basis, contains alkaloids in the amounts shown in Table 1.
TABLE 1opiumstrawmorphine, %10-161-3codeine, %0.8-2.50.05-0.3 oripavine, %  0-0.1  0-0.05thebaine, %0.5-2  0.15-0.65
As can be seen, the yield of codeine is confounded with that of other alkaloids. A poppy producing predominantly codeine, e.g., as 55% or more of the total alkaloids, would enable a simpler extraction/purification process, resulting in higher yields, better quality and throughput and lower costs.
Where solvent or water or super critical fluid, such as CO2, extraction is employed to remove the alkaloids from the straw, such method, as practiced, involves the production of “Concentrate of Poppy Straw”. Concentrate of Poppy Straw (or “CPS”) is described as “The material arising when poppy straw has entered into a process for the concentration of its alkaloids, when such material is made available in trade,” (Multilingual dictionary of narcotic drugs and psychotropic substances under international control, United Nations, New York, 1983). Not inconsistent with the foregoing description, Concentrate of Poppy Straw is described as “the crude extract of poppy straw in either liquid, solid or powder form which contains the phenanthrene alkaloids of the opium poppy,” 45 U.S. Federal Register 77466, Nov. 24, 1980. When in liquid form, the liquid is preferably concentrated before entering into commerce. The generally preferred Concentrate of Poppy Straw is the powder form which results from removing the solvent or water following extraction of the poppy straw. According to the United Nations publication ‘Narcotic Drugs: Estimated World Requirements for 2007; Statistics for 2005 (E/INCB/2006/2)’, “Concentrate of Poppy Straw is the dried residue obtained through the extraction of alkaloids from poppy straw. Until the second half of the 1990s, only concentrate of poppy straw containing morphine as the main alkaloid was manufactured. Since then, concentrate of poppy straw containing mainly thebaine or oripavine has started to be manufactured.”
Some relatively small quantities of CPS codeine are produced in a few countries as a by-product of CPS morphine extraction. These quantities are not significant in world trade. The claimed invention now provides codeine CPS which has great commercial potential because it allows production of codeine CPS and derivatives without the need to grow poppies containing morphine.